DAXX/ATRX, MEN1 and mTOR Pathway Genes are Frequently Altered in Pancreatic Neuroendocrine Tumors

Authors

Jiao Y

Shi C

Edil BH

de Wilde RF

Klimstra DS

Maitra A

Schulick RD

Tang LH

Wolfgang CL

Choti MA

Velculescu VE

Diaz LA Jr

Vogelstein B

Kinzler KW

Hruban RH

Papadopoulos N

Doi

10.1126/science.1200609

PMID: 21252315 · DOI: 10.1126/science.1200609 · Journal: Science (2011)

TL;DR

Whole-exome sequencing of 10 sporadic pancreatic neuroendocrine tumors (PanNETs) followed by targeted Sanger validation in 58 additional cases revealed that chromatin-remodeling genes are the most frequently mutated: MEN1 in 44% and DAXX/ATRX in 43% of tumors. mTOR pathway genes (PTEN, TSC2, PIK3CA) were mutated in 14%. Mutations in MEN1 and DAXX/ATRX were associated with significantly better prognosis, and mTOR pathway mutations suggest a rationale for patient stratification for everolimus therapy.

Cohort & data

  • 68 sporadic, non-familial PanNETs (Discovery set n=10, Validation set n=58) from Johns Hopkins and Memorial Sloan-Kettering Cancer Center.
  • Cancer type: PANET.
  • Dataset: panet_jhu_2011.
  • Assays: whole-exome-seq (Discovery set, Illumina GAIIx with SureSelect capture, mean 101x coverage) and sanger-sequencing (Validation set, targeted genes).
  • Tumors microdissected to >80% neoplastic cellularity; small cell and large cell neuroendocrine carcinomas excluded.

Key findings

  • Mean somatic mutation burden was 16 mutations per tumor (range 8-23) across ~18,000 genes in the Discovery set; 91% validated by Sanger sequencing.
  • MEN1 mutated in 44.1% (30/68) of PanNETs; 25 of 30 mutations were inactivating (indels, nonsense, splice-site), establishing it as a tumor suppressor in this context.
  • DAXX mutated in 25% (17/68) and ATRX in 17.6% (12/68); mutations were mutually exclusive (never co-occurring in the same tumor). Combined DAXX/ATRX pathway alteration rate: 42.6% (29/68).
  • mTOR pathway genes mutated in 14%: PTEN 7.3% (5/68), TSC2 8.8% (6/68), PIK3CA 1.4% (1/68).
  • PanNETs have a distinct genetic landscape from pancreatic ductal adenocarcinoma (PDAC): KRAS 0% vs 100%, TP53 3% vs 85% in PDAC; 60% fewer mutations per tumor than PDAC.
  • Mutation spectra differ: C>G transversions more common in PanNETs, C>T transitions more common in PDACs.

Genes & alterations

  • MEN1: Inactivating mutations (indels, nonsense, splice-site) in 44% of PanNETs. Encodes menin, a component of MLL/SET1-like histone methyltransferase complex. Biallelic inactivation documented.
  • DAXX: Inactivating mutations in 25%. H3.3-specific histone chaperone. Loss of immunolabeling correlated with mutation status.
  • ATRX: Inactivating mutations in 17.6%. Partners with DAXX for H3.3 incorporation at telomeres. Missense mutations clustered in the conserved helicase domain.
  • PTEN: 7.3% (2 indels, 3 missense). mTOR pathway tumor suppressor.
  • TSC2: 8.8% (1 indel, 1 nonsense, 4 missense). mTOR pathway negative regulator.
  • PIK3CA: 1.4% (1 missense, K545E). mTOR/PI3K pathway oncogene.

Clinical implications

  • Mutations in MEN1 and/or DAXX/ATRX are associated with prolonged survival. In patients with metastatic disease harboring both MEN1 and DAXX/ATRX mutations, 100% survived at least 10 years, versus >60% death within 5 years in mutation-negative patients.
  • mTOR pathway mutations (14% of PanNETs) provide a genetic rationale for stratifying patients for treatment with everolimus (RAD-001), which had shown increased progression-free survival in advanced PanNET patients (RADIANT-3 trial referenced).
  • Mutational status of MEN1, DAXX, and ATRX could serve as prognostic biomarkers for PanNET clinical management.

Limitations & open questions

  • Relatively small cohort (n=68); survival analyses lack multivariate adjustment for stage and grade.
  • Only sporadic PanNETs studied; familial syndrome-associated tumors excluded, limiting generalizability.
  • mTOR pathway mutations found at genetic level in 14%, but expression-level alterations reported more broadly — the predictive value of genotype for everolimus response remains unproven.
  • Contaminating normal DNA made it difficult to reliably distinguish heterozygous from homozygous changes in some cases.
  • Functional validation of DAXX/ATRX as tumor suppressors in PanNET models not performed in this study.

Citations from this paper used in the wiki

  • “44% of the tumors had somatic inactivating mutations in MEN-1 … and 43% had mutations in genes encoding either of the two subunits of a transcription/chromatin remodeling complex consisting of DAXX … and ATRX” (Abstract).
  • “mutations in the MEN1 and DAXX/ATRX genes were associated with better prognosis” (Abstract).
  • “100% of patients with PanNETs that had these mutations survived at least ten years while over 60% of the patients without these mutations died within five years of diagnosis” (p. 4).
  • “We also found mutations in genes in the mTOR … pathway in 14% of the tumors, a finding that could potentially be used to stratify patients for treatment with mTOR inhibitors” (Abstract).

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